Glioblastoma (GBM) are the most malignant primary brain tumor and patients with GBM (grade IV glioma) have a survival time of approximately 14 months. Estrogen plays a crucial role during brain development and differentiation. Epidemiological and experimental evidence suggests tumor suppressive role of estrogen on brain tumors. However, the molecular mechanisms by which estrogen mediate protection against GBM remains unknown. Estrogen functions are mediated by two ER-subtypes: ER that functions as tumor promoter and ER that functions as a tumor suppressor. Emerging evidence suggest that GBM cells express ER; however, the clinical utility of ER is limited due to lack of mechanistic insights and agents that specifically target ER. Recent studies have identified liquiritigenin (LIQ) isolated from the plant Glycyrrhiza uralensis and synthetic compound LY500307 (LY) as selective ER specific agonists. The objective of this proposal is to translate evolving scientific evidence and the functional role of ER into a clinical strategy to suppress GBM by employing ER specific agonists. Our central hypothesis is that ER agonists inhibit the growth of GBM by enhancing tumor suppressive functions of ER and that ER agonists promote differentiation of glioma stem cells leading to increased therapeutic efficacy. The hypothesis is supported by our preliminary studies that (1) ER-mediated mechanisms play a tumor suppressive function; (2) ER agonists suppress GBM cell proliferation in vitro and in vivo; (3) ER-agonists upregulate expression of ER (4) ER-agonists inhibit growth of Glioma Stem Cells and promote their differentiation. To investigate the proposed hypotheses, in aim 1, we will test the significance and therapeutic efficacy of ER agonists to inhibit the growth of GBM. In aim 2, we will determine the molecular mechanism(s) of ER agonists in the suppression of GBM. In aim 3, we will investigate the role of ER agonists in the differentiation of Glioma Stem Cells. Understanding how ER functions as a tumor suppressor in GBM will be useful in maximizing treatment opportunities for GBM. The proposed research is innovative due to the novelty of the concepts involving ER agonists and their therapeutic potential in the suppression of GBM. This proposal will establish the significance and therapeutic potential of ER signaling in GBM progression and thus create a new paradigm for the use of ER specific ligands (LIQ and LY) for curbing GBM progression. Since ER agonists currently in clinical trials are well tolerated with limited side effects and good blood-brain barrier permeability, identification of ER agonists as a therapeutic agent can be readily adapted to clinical use as a monotherpy or in combination with current chemotherapies and radiation, thereby providing an additional tool for enhancing survival in GBM patients. Further, the results from these studies have the potential to provide novel insights into the mechanisms of ER mediated tumor suppression at the molecular level.